We are investigating extrahepatic biliary motility as it pertains to enterohepatic cycling of bile salts and bile composition. There is evidence that changes in enterohepatic circulatory dynamics may be involved in the pathogenesis of gallstones. Using the hysteresis methodology, we demonstrated that CCK-OP and vagal stimulation significantly decreased baboon gallbladder compliance, and that when the two are combined, the decrease compliance was more marked. We also investigated methodologies for accurately and reliably measuring distal choledochal sphincter resistance and found a constant perfusion method to be most reliable in the awake baboon. Using this methodology, we demonstrated that CCK-OP raised sphincter resistance when given as a bolus; however, when infused, sphincter resistance fell. Using the same methodology, we found that histamine reduces sphincter resistance; specific H1 and H2 agonists suggest that the effects is mediated by H2 receptors in the sphincter. Using in-vitro guinea pig gallbladder muscle, we demonstrated that H1 receptors stimulate gallbladder contraction and that H2 receptors cause relaxation. Kinetic analysis reveals that histamine is bound preferentially to H2 receptors, suggesting that low tissue levels of histamine would favor relaxation, while higher levels would produce contraction. In-vivo baboon experiments with specific H1 and H2 agonists confirmed the role of these receptors in primates.